An anti-leukemia/lymphoma effect can be achieved by infusing allogeneic lymphocytes from bone marrow, blood or spleen of healthy donors into tumour bearing recipients (Bortin et al (1989); Korngold et al. (1994)). The ability of infused lymphocytes to prevent leukemia relapse is termed graft-versus-leukemia (GVL), and is often attributed to the allogeneic portion of the infused lymphocytes. However, the infused foreign lymphocytes, can also respond to the major and minor histocompatibility (MHC and mH, respectively) antigens expressed on host cells and cause graft versus host disease (GVHD) which represents a major factor responsible for the death of recipients (Sprent et al. (1986); Ferrara et al. (1991)). In class I mismatched models, CD8+ T cells contribute significantly to GVHD (Korngold et al. (1985); Champlin et al. (1991)). In order to reduce the severity of GVHD, lymphocytes from donors that are matched for MHC antigens with the recipients have been used in conjunction with non-specific immunosuppression. Although these approaches decrease the incidence and severity of GVHD, they also reduce marrow engraftment and increase leukemia relapse (Korngold et al. (1994); Kolb et al. (1995); Barrett et al. (1996)). While multiple cell types, including CD4+, CD8+ and NK T cells have been shown to play a role in GVL (Champlin (1992); Imamura et al. (1996); Zeis et al. (1997)); Hauch et al. (1990); van Lochem et al. (1992); Sykes et al. (1994); Palathumpat et al. (1992); Palathumpat et al. (1995)), it remains uncertain whether the cells that contribute to GVHD are distinct from those that kill tumour cells (Champlin (1992); van Lochem et al. (1992); Apperley et al. (1986); Prentice et al. (1984); Horowitz et al. (1990); Pan et al. (1999)). Consequently, a goal of bone marrow tranplantation is to identify and augment those cells with a beneficial GVL effect that do not contribute to GVHD.
Accumulating evidence indicate that T regulatory (Tr) lymphocytes play an important role in down-regulation of immune responses to self or allogeneic antigens (Qin et al. (1993); Groux et al. (1997); Zhang et al. (2000); Han et al (1996); Ierino et al. (1999); Cobbold et al. (1998) Bushell et al. (1999); Baxter et al. (1997); Lancaster et al. (1985); Chai et al. (1999); Zhai et al. (1999); Sakaguchi (2000); Roncarolo et al. (2000)). Whether Tr cells play a role in GVHD/GVL, however, remains unclear. The inventors and others have demonstrated that pre-transplantation donor-specific transfusion (DST) of one MHC class I or class II mismatched lymphocytes leads to permanent acceptance of the skin or cardiac allografts of the lymphocyte donor origin (Yang et al. (1999); van Twuyver et al. (1989); van Twuyver et al. (1990)). Because all third party allografts were promptly rejected by the recipients after DST, it indicates that the tolerance induced by one MHC locus-mismatched lymphocytes is antigen-specific, and the recipients retained their immune responses to other alloantigens. Furthermore, from the recipients who have received DST and permanently accepted donor skin allografts, the inventors have recently identified a novel CD4−CD8− double negative (DN) Tr cells which differs from any previously reported Tr cells in terms of their surface marker expression, cytokine profile and mechanism of suppression (Zhang et al. (2000)). The inventors also demonstrated that the DN Tr cells are able to kill activated CD8+ T cells that carry the same TCR specificity (Zhang et al. (2000)).
There is a need in the art to identify cells involved in tumor immunity that are useful in developing anti-cancer therapies.